This invention relates to a method for the prevention and treatment of stunned heart phenomenon. Particularly, the invention relates to a method for the prevention and treatment of stunning of the myocardium in association with ischemia-reperfusion. The cardiovascular interventions and conditions accompanied with the ischemia-reperfusion and subsequent stunning include e.g. thrombolysis of myocardial infarction, coronary balloon angioplasty and coronary stent implantation, coronary artery bypass surgery and other open-heart operations, coronary atherectomy, unstable angina, heart transplantation, resuscitation and valvular heart disease. The method for the prevention or treatment of stunned myocardium comprises administering a phosholamban inhibitor as the active compound.
The contraction of cardiac muscle cell is caused by calcium ions released from the intracellular calcium stores of the sarcoplasmic reticulum (SR). After triggering a cascade of events leading to cell shortening and muscle contraction a major part of calcium is reuptaken to the SR by the enzyme called Ca.sup.2+ ATPase and a minor part of calcium is extruded out of the cell. The Ca.sup.2+ ATPase is functioning under the inhibitory control of a small protein called phospholamban. The unphosphorylated form of phospholamban inhibits the Ca.sup.2+ ATPase. The phosphorylation of phospholamban relieves this inhibition which is then seen as a stimulation of the Ca.sup.2+ ATPase. The relief of the phospholamban inhibition on the Ca.sup.2+ ATPase stimulates the uptake of calcium from the cytoplasm into the SR which then finally increases the amount of calcium for the next contraction. In addition to the phosphorylation based regulation the inhibition of the Ca.sup.2+ ATPase by phospholamban can be eliminated also by compounds which directly bind to phospholamban. Such compounds (phospholamban inhibitors) eliminate the inhibitory action of phospholamban on the SR Ca.sup.2+ -ATPase like the protein kinases as they phosphorylate phospholamban.
One of the pathological phenomena in the function of the heart is called stunned myocardium in which the contraction force is decreased despite the normal coronary flow. The stunning is developed as a consequence of the ischemic period (=marked decrease in the coronary flow) followed by reperfusion of the myocardium. It is typical that in the stunned myocardium the decreased contraction force is not accompanied with the decrease in the amount of calcium released from the SR. On the contrary, there is higher amount of calcium in the SR available for contraction trigger in stunned myocardium (Marban, E., "Myocardial stunning and hibernation. The physiology behind the colloquialisms", Circulation, 83(2):681-688, 1991). Therefore, the stimulation of the calcium uptake into the SR is not expected to change the stunning in the myocardium.